Kaposi's sarcoma (KS) is the most common cancer in AIDS patients associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KS is often involved with oral cavity, and oral KSHV infection is necessary for the development of oral KS and virus spread. Despite antiretroviral therapy, KS remains common among HIV-infected patients. Existing antiviral and anticancer therapies are ineffective for eliminating persistent KSHV infection and for treating KSHV-induced cancer. Because KSHV latent infection is necessary for its long-term persistent infection and for KS development, identificatio of factors essential for KSHV latent infection can lead to the development of novel therapeutic approaches for oral KSHV persistent infection and malignancies. We have developed three novel systems to address these challenges: 1) KSHV-induced cellular transformation of primary human bone marrow mesenchymal stem cells (MSCs), 2) KSHV persistent infection in the oral cavity in NOD/SCID IL2R?-/- (NSG) humanized mice, and 3) KSHV persistent infection in primary human oral epithelial cells, gingiva MSCs and dental pulp MSCs. Using these models, we have found extensive epigenetic reprograming of cellular chromatins and gene expression networks in latent KSHV- infected cells. Furthermore, we have identified histone modifiers including polycomb repressive complex 2 (PRC2) proteins and class III histone deacetylases sirtuins as the critical factors for the survival of latent KSHV-infected cells. Significantly, targeting PRC2 proteins and sirtuins induce massive cell death of latent KSHV-infected cells including KSHV-transformed cells but have minimal cytotoxicity to uninfected cells. Based on these results, our hypothesis is that histone modifiers mediate the survival of latent KSHV-infected oral cells, and therefore inhibition of these targets can kill latent KSHV-infected cells resulting in effective therapeutic intervention for oral KSHV persistent infection and KSHV-induced cancer. We propose to identify the histone modifiers essential for KSHV latent infection in oral cells (Aim 1); delineate the mechanisms by which histone modifiers mediate the survival of latent KSHV infected oral cells (Aim 2); and therapeutically clear oral KSHV persistent infection and inhibit KSHV-induced oral cancer in animal models by targeting specific histone modifiers (Aim 3). The proposed project is significant because it will delineate the essential histone modifiers for oral KSHV persistent infection and pathogenesis, and identify effective inhibitors for therapeutic inhibition of these novel targets. The results will provide insights int the mechanisms of oral KSHV persistent infection and KSHV-induced oncogenesis. The outcomes can also be applied to other oral persistent viral infections and virus-induced cancer.